Vascular diseases are among the most common causes of morbidity and mortality in the Western world. A remarkable feature of these disorders is the local nature of their distribution; virtually all diseases are associated with focal vasculopathy is found within the endothelium. Endothelial cell phenotypes are differentially regulated in space and time. Endothelial cell heterogeneity is mediated by a combination of genetic and microenvironmental determinants. The very existence of spatial and temporal heterogeneity, along with the combined role for genetic predetermination and the environment necessitates a multidisciplinary approach. The overall goal of this is to map and delineate the mechanisms of phenotypic heterogeneity in health and disease states. Project 1 will focus on the modular regulation of endothelial cell-specific genes expression in the intact vascular tree. Project 2 will study mechanisms of endothelial cell differentiation, with particular focus on the role of transcription factors and the molecular characterization and modulation of endothelial precursors in myocardial ischemia. Project 3 will characterize the role of NDPases in site-specific endothelial cell biology. Project 4 will employ sickle cell disease and stroke as a model to examine the role of genetic heterogeneity in human endothelial gene expression. Core A (Administration) will provide administrative, secretarial and laboratory management support for the program. Histology Core will assist in the processing of tissues for immunohistochemistry, in situ hybridization and histopathologic examination. Core (Genomics and Bioinformatics) will support DNA arrays and bioinformatics. Core (Stem Cell Support) will provide assistance with ES cell differentiation, including embryoid bodies. Core (Viral Development will be concerned with development and construction of adenoviruses for the program).